Recombinant EGFR/MMP-2 bi-targeted fusion protein markedly binding to non-small-cell lung carcinoma and exerting potent therapeutic efficacy.

Abstract

Overexpression of EGFR and MMP-2 plays an essential role in the initiation and progression of non-small-cell lung carcinoma (NSCLC). In this study, a novel format of EGFR/MMP-2 bi-targeted fusion protein Ec-LDP-TIMP2 and its enediyne-integrated analogue Ec-LDP(AE)-TIMP2 have been prepared by genetic engineering and molecular reconstitution. The Ec-LDP(AE)-TIMP2 comprises endogenous inhibitor of matrix metalloproteinase 2 (TIMP2), EGF-derived oligopeptide (Ec), lidamycin apoprotein (LDP), and the extremely potent cytotoxic enediyne (AE). By tissue microarray, Ec-LDP-TIMP2 showed high binding intensity and selectivity to human NSCLC specimens as compared with the matched non-cancerous tissues. By in vivo imaging, Ec-LDP-TIMP2 displayed prominent tumor-specific distribution in human NSCLC H460 xenograft. Particularly, Ec-LDP(AE)-TIMP2 inhibited tumor growth of H460 xenograft in athymic mice more striking. At doses of 0.2 and 0.4mg/kg, Ec-LDP(AE)-TIMP2 suppressed tumor growth by 74% and 89%, respectively. No histopathological changes were found in various organs of treated animals, suggesting that the effective dosage was tolerated. In summary, the ligand-based and enediyne-integrated fusion protein displaying extremely potent cytotoxicity might be highly effective for NSCLC therapy and useful as a carrier for drug delivery.

• Authors: Jian Xu, Yue Du, Xiu-Jun Liu, Bing-Yan Zhu, Sheng-Hua Zhang, Liang Li, Yi Li, Xiao-Fei Wang, Chuan-Kun Shan, Rui-Qi Wang, Yong-Su Zhen
• Journal: Pharmacological research (Pharmacol Res) Vol. 126 Pg. 66-76 (Dec 2017) ISSN: 1096-1186 [Electronic] Netherlands
• PMID: 28392461 (Publication Type: Journal Article)
• Copyright: Copyright © 2017 Elsevier Ltd. All rights reserved.

Chemical References

• Antineoplastic Agents
• Ligands
• Matrix Metalloproteinase Inhibitors
• Oligopeptides
• Recombinant Fusion Proteins
• Tissue Inhibitor of Metalloproteinase-2
• EGFR protein, human
• ErbB Receptors
• Matrix Metalloproteinase 2

Topics

• A549 Cells
• Animals
• Antineoplastic Agents (pharmacology)
• Carcinoma, Non-Small-Cell Lung (drug therapy, metabolism)
• Cell Line, Tumor
• ErbB Receptors (antagonists & inhibitors)
• Female
• Humans
• Ligands
• Lung Neoplasms (drug therapy, metabolism)
• Matrix Metalloproteinase 2 (metabolism)
• Matrix Metalloproteinase Inhibitors (pharmacology)
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Oligopeptides (pharmacology)
• Recombinant Fusion Proteins (pharmacology)
• Tissue Inhibitor of Metalloproteinase-2 (pharmacology)
• Xenograft Model Antitumor Assays (methods)